Arthur Kavanaugh

Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial

Background: Certolizumab pegol is a PEGylated tumour necrosis factor inhibitor. Objective: To evaluate the efficacy and safety of certolizumab pegol versus placebo, plus methotrexate (MTX), in patients with active rheumatoid arthritis (RA). Methods: An international, multicentre, phase 3, randomised, double-blind, placebo-controlled study in active adult-onset RA. Patients (nu200a=u200a619) were randomised 2:2:1 to subcutaneous certolizumab pegol (liquid formulation) 400 mg at weeks 0, 2 and 4 followed by 200 mg or 400 mg plus MTX, or placebo plus MTX, every 2 weeks for 24 weeks. The primary end point was ACR20 response at week 24. Secondary end points included ACR50 and ACR70 responses, change from baseline in modified Total Sharp Score, ACR core set variables and physical function. Results: Significantly more patients in the certolizumab pegol 200 mg and 400 mg groups achieved an ACR20 response versus placebo (p⩽0.001); rates were 57.3%, 57.6% and 8.7%, respectively. Certolizumab pegol 200 and 400 mg also significantly inhibited radiographic progression; mean changes from baseline in mTSS at week 24 were 0.2 and −0.4, respectively, versus 1.2 for placebo (rank analysis p⩽0.01). Certolizumab pegol-treated patients reported rapid and significant improvements in physical function versus placebo; mean changes from baseline in HAQ-DI at week 24 were −0.50 and −0.50, respectively, versus −0.14 for placebo (p⩽0.001). Most adverse events were mild or moderate, with low incidence of withdrawals due to adverse events. Five patients developed tuberculosis. Conclusion: Certolizumab pegol plus MTX was more efficacious than placebo plus MTX, rapidly and significantly improving signs and symptoms of RA and physical function and inhibiting radiographic progression. Trial registration number: NCT00175877

LB0003 Tocilizumab (TCZ) monotherapy is superior to adalimumab (ADA) monotherapy in reducing disease activity in patients with rheumatoid arthritis (RA): 24-week data from the phase 4 adacta trial

Background Approximately 1/3 of RA patients (pts) on biologics receive them as monotherapy (without other DMARDs) [1,2]. TCZ, an inhibitor of IL-6 receptor signalling, has been studied as monotherapy in 3 clinical trials [3–5], but direct comparison with an anti-TNF agent has not previously been performed. Objectives To evaluate efficacy and safety of TCZ vs the anti-TNF agent ADA, both given as monotherapy, in RA pts with DAS28 >5.1. Methods ADACTA was a multicentre, randomised, double-blind, 24-wk study designed specifically to test superiority in pts with RA of ≥6-mo duration who were MTX intolerant or for whom continued treatment with MTX was inappropriate. Pts were randomly assigned (1:1) to TCZ 8 mg/kg IV every 4 wks (+ placebo ADA) or ADA 40 mg subcutaneously (SC) every 2 wks (+ placebo TCZ) for 24 wks. Escape to wkly SC ADA/placebo was permitted at wk 16; 10 ADA and 7 TCZ pts escaped. The primary endpoint was mean change from baseline (BL) in DAS28 at 24 wks. Results The intent-to-treat population included 325 pts (163 TCZ, 162 ADA). BL characteristics were similar between the TCZ and ADA arms: mean age 54.4 and 53.3 y, mean RA duration 7.3 and 6.3 y and mean DAS28 6.72 and 6.76, respectively. Efficacy at wk 24: mean change from BL in DAS28 was significantly greater with TCZ (–3.3) than with ADA (–1.8) (Table). A numerical difference between the 2 arms in swollen and tender joint counts, ESR and patient global assessment in favour of TCZ was seen from wk 8 onward. Statistical significance was also achieved in favour of TCZ for DAS28 remission and low disease activity (LDA), and ACR20/50/70 responses (Table). Safety: the incidence of adverse events (AEs) was similar between groups (TCZ: 82.1%; ADA: 82.7%). Serious AEs and serious infections also were similar (TCZ: 11.7%, 3.1%; ADA: 9.9%, 3.1%). Changes in laboratory values, including transaminase and LDL elevations and neutrophil reductions, occurred in both arms, with the proportion of pts with abnormal values higher in the TCZ arm. There were 2 deaths, both in the TCZ arm: 1 from sudden death, the other from reported illicit drug overdose. Table 1. Selected Efficacy Endpoints at Wk 24 (intent-to-treat populationa) TCZ, n=163 ADA, n=162 pb Primary: change from BL in DAS28 –3.3c –1.8 (diff: –1.5) <0.0001 DAS28 remission, % 39.9 10.5 <0.0001 DAS28 LDA, % 51.5 19.8 <0.0001 ACR20, % 65.0 49.4 <0.01 ACR50, % 47.2 27.8 <0.01 ACR70, % 32.5 17.9 <0.01 aLOCF and NR imputation were applied to continuous and categorical endpoints, respectively, to handle missing data and data after withdrawal and escape. bp values were adjusted for region and duration of RA for all endpoints and additionally baseline DAS28 for the primary endpoint. cTwo pts in the TCZ arm with no post-baseline data were excluded from the primary endpoint analysis. Conclusions Monotherapy with TCZ was superior to monotherapy with ADA in reducing signs and symptoms of RA in MTX-intolerant pts or pts for whom MTX treatment was considered ineffective or inappropriate. The overall safety profile of both medications was consistent with previously reported data. References Yazici, Bull NYU Hosp Jt Dis 2008;66:77. Soliman, Ann Rheum Dis 2011;70:583. Dougados Arthritis Rheum 2011 63(Suppl):S1032. Weinblatt Arthritis Rheum 2011 63(Suppl):S864. Jones Ann Rheum Dis 2010;69:88. Disclosure of Interest C. Gabay Consultant for: Roche, Abbott, Merck, UCB, Pfizer, BMS, Merckserono, Novartis, Amgen, Speakers Bureau: Roche, Abbott, Merck, UCB, Pfizer, BMS, Merckserono, Novartis, Amgen, P. Emery Consultant for: Merck, Abbott, Pfizer, Roche, UCB, BMS, R. van Vollenhoven Grant/Research support from: Abbott, GSK, MSD, Pfizer, Roche, UCB, Consultant for: Abbott, GSK, MSD, Pfizer, Roche, UCB, A. Dikranian Speakers Bureau: Genentech, UCB, Abbott, BMS, R. Alten Grant/Research support from: BMS, Novartis, Pfizer, Roche, UCB, Consultant for: Abbott, BMS, Novartis, Pfizer, Roche, UCB, Speakers Bureau: Abbott, BMS, Novartis, Pfizer, Roche, UCB, M. Klearman Employee of: Genentech, a member of the Roche group, D. Musselman Employee of: Genentech, a member of the Roche group, S. Agarwal Shareholder of: Genentech, a member of the Roche group, Employee of: Genentech, a member of the Roche group, J. Green Shareholder of: Roche, Employee of: Roche, A. Kavanaugh Grant/Research support from: Roche, Amgen, Abbott, BMS, Janssen, UCB, Pfizer

THU0202 Clinical Responses and Improvements in Patient-reported Outcomes are Associated with Increased Productivity in the Workplace and at Home in Axial Spondyloarthritis Patients Treated with Certolizumab Pegol

Background Axial spondyloarthritis (axSpA) includes patients (pts) with both ankylosing spondylitis (AS) and non-radiographic axSpA (nr-axSpA).1 AS significantly affects pt workplace productivity, both in terms of performance and disease-related absenteeism.2 By contrast, the impact of nr-axSpA on productivity is less well characterized. Furthermore, there are few studies on the association between improvements in workplace and household productivity and symptom relief with available therapies in axSpA pts. Objectives To evaluate the association between improvements in clinical and pt-reported outcomes (PROs) and improvements in productivity in the workplace and at home in axSpA pts treated with certolizumab pegol (CZP), including AS and nr-axSpA pts. Methods Associations between clinical outcomes or PROs and work and household productivity outcomes were made using Wk24 data from the double-blind and placebo-controlled period of RAPID-axSpA (NCT01087762),3 for pts originally randomized to CZP. Clinical outcomes included achievement of ASAS40 and ASDAS MI responses. PROs included achievement of MCID for BASFI (≥1 decrease from baseline [BL]), total back pain (≥1 decrease from BL) and ASQoL (≥2 decrease from BL). Responders and non-responders at Wk24 for clinical outcomes and PROs were compared in terms of change from BL (CFB) in workplace and household productivity, as assessed using the validated arthritis-specific Work Productivity Survey (WPS).4 Groups were compared using a non-parametric bootstrap-t method. Missing data were imputed using last observation carried forward for WPS outcomes and non-responder imputation for clinical outcomes and PROs. Results 218 CZP pts entering RAPID-axSpA were included in Wk24 analyses, including 121 AS and 97 nr-axSpA pts. 73.9% axSpA, 73.6% AS and 74.2% nr-axSpA pts were employed at Wk24. Overall, pts achieving a clinical or PRO response at Wk24 reported greater improvements in workplace and household productivity than non-responders (Table). Improvements in ASQoL and clinically meaningful reductions in functional limitation and pain were associated with improved workplace absenteeism and presenteeism. Greater improvements in productivity were seen in responders vs non-responders in both AS and nr-axSpA subpopulations. Numerically greater CFB was seen in nr-axSpA pts, potentially due to the slightly higher BL productivity burden of nr-axSpA vs AS.5 Responders also reported greater improvements in participation in family, social and leisure activities (not shown). Results should be interpreted with caution, due to differences in the number of pts between groups and because analyses were not adjusted for differences in BL productivity. Conclusions Clinical responses and clinically meaningful improvements in PROs are associated with improved workplace and household productivity in axSpA pts treated with CZP, including both AS and nr-axSpA pts. References Boonen A. Ann Rheum Dis 2010;69:1123–1128. van der Heijde D. Ann Rheum Dis 2013;72:87. Landewé R. Ann Rheum Dis 2014;73:39–47. Osterhaus J. Arthritis Res Ther 2014;16:R164. van der Heijde D. Ann Rheum Dis 2013;72:523–524. Disclosure of Interest D. van der Heijde Grant/research support from: AbbVie, Amgen, AstraZeneca, Augurex, BMS, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GSK, Janssen, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, UCB Pharma, Vertex, Consultant for: AbbVie, Amgen, AstraZeneca, Augurex, BMS, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GSK, Janssen, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, UCB Pharma, Vertex, Employee of: Director of Imaging Rheumatology bv, J. Braun Grant/research support from: Abbott, Bristol Myers Squibb, Celgene, Celltrion, Chugai, Johnson & Johnson, MSD, Novartis, Pfizer, Roche, UCB Pharma, Consultant for: Abbott, Bristol Myers Squibb, Celgene, Celltrion, Chugai, Johnson & Johnson, MSD, Novartis, Pfizer, Roche, UCB Pharma, M. Rudwaleit Consultant for: Abbott, BMS, MSD, Pfizer, Roche, UCB Pharma, O. Purcaru Employee of: UCB Pharma, A. Kavanaugh Grant/research support from: Abbott, Amgen, BMS, Pfizer, Roche, Janssen, UCB Pharma

AB0235 Effect of baseline disease activity on achieving sustained low disease activity in baricitinib phase 3 studies

Background In the Phase 3 studies RA-BUILD1 and RA-BEAM2, baricitinib (bari) has demonstrated clinical efficacy including reduced disease activity in RA patients (pts) with an inadequate response (IR) to conventional synthetic DMARDs (csDMARDs). Objectives To determine whether disease activity at baseline (BL) affects the achievement of sustained low disease activity (LDA) with bari treatment. Methods In this post hoc analysis, pts from the placebo (PBO) and bari 4 mg treatment arms of the RA-BUILD and RA-BEAM studies were categorised based on their level of disease activity at BL; either CDAI ≤median or CDAI >median, where median was 34.8 for RA-BUILD and 36.2 for RA-BEAM. Pts who achieved CDAI ≤10 at ≥2 consecutive visits (sustained LDA) within 12 and 24 weeks (wks) were considered as responders. The length of time required by pts to achieve sustained LDA was determined for each group using the incidence rate (percent pts responding per month). In addition, the association between response and dose of bari was explored in csDMARD-IR pts randomised to bari (2 mg or 4 mg) once daily from the RA-BUILD study. Results Within the bari 4 mg arm, a greater proportion of pts with CDAI ≤median at BL achieved sustained LDA and within a shorter treatment duration as indicated by higher incidence rates, compared to pts with CDAI >median at BL. In pts with CDAI ≤34.8 at BL, the 2 mg and 4 mg doses showed similar efficacy, but a larger proportion of pts with CDAI >34.8 reached sustained LDA at 24 wks with bari 4 mg than 2 mg (41.4% and 32.4%, respectively).Table 1. Proportions and Rates of Sustained LDA Achievement with Baricitinib Treatment Pts achieving CDAI ≤10 BL CDAI ≤ median BL CDAI > median PBO Bari 4 mg Bari 2 mg PBO Bari 4 mg Bari 2 mg RA-BUILD N 116 108 114 108 116 111 u2003Wk12 % 19.8 42.6 40.4 7.4 21.6 18.0 i-rate 4.36 11.78 10.50 1.55 4.69 3.90 u2003Wk24 % 44.8 63.9 63.2 17.6 41.4 32.4 i-rate 10.63 19.20 17.59 3.80 9.59 7.27 RA-BEAM N 249 236 235 246 u2003Wk12 % 23.7 39.8 4.3 18.7 i-rate 2.71 5.40 0.42 1.98 u2003Wk24 % 34.5 69.1 14.0 41.9 i-rate 4.35 12.97 1.49 5.47 Pts were defined as responders if they met the response criterion within the stated time frame, prior to any rescue or discontinuation. % = percent of pts meeting response criteria; CDAI median = 34.8 (RA-BUILD) or 36.2 (RA-BEAM); i-rate = exposure-adjusted incidence rate (% pts/month); N = number of randomised and treated pts. Conclusions Pts with CDAI ≤35–36 at BL achieved sustained LDA more frequently and more rapidly than pts in the higher disease category at BL. In pts with higher disease activity at BL a more robust response was observed with bari 4 mg treatment. References Dougados M et al. Ann Rheum Dis 2017; 76(1):88–95. Taylor P et al. Arthritis Rheumatol 2015; 67(Suppl 10):1–4046. Disclosure of Interest J. Curtis Grant/research support from: AbbVie, Amgen, BMS, Corrona, Eli Lilly and Company, Janssen, Myriad, Pfizer, Roche/Genentech, UCB, Consultant for: AbbVie, Amgen, BMS, Corrona, Eli Lilly and Company, Janssen, Myriad, Pfizer, Roche/Genentech, UCB, A. Kavanaugh Consultant for: Eli Lilly and Company, D. van der Heijde Consultant for: AbbVie, Amgen, Astellas, Astra-Zeneca, BMS, Boeringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly and Company, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi-Aventis, UCB, Employee of: Director of Imaging Rheumatology bv, D. Muram Employee of: Eli Lilly and Company, J. Alam Employee of: Eli Lilly and Company, J. Smolen Grant/research support from: Abbvie, Janssen, Eli Lilly and Company, MSD, Pfizer, Roche, Consultant for: Abbvie, Amgen, Astra-Zeneca, Astro, BMS, Celgene, Celltrion, Chugai, Gilead, Glaxo, ILTOO, Janssen, Eli Lilly and Company, Medimmune, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi-Aventis, UCB, Speakers bureau: Abbvie, Amgen, Astra-Zeneca, Astro, BMS, Celgene, Celltrion, Chugai, Gilead, Glaxo, ILTOO, Janssen, Eli Lilly and Company, Medimmune, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi-Aventis, UCB

THU0110 The importance of sustained remission for longterm outcomes in patients with rheumatoid arthritis

Background In patients (pts) with rheumatoid arthritis (RA), the long-term impact of sustained versus (vs) transient clinical remission (REM) has not been assessed thoroughly, although REM duration has been shown to affect structural outcomes1. The relationship of different definitions of clinical remission (REM) with function and structural integrity has not been assessed. Objectives To explore the importance of sustained REM or disease control for long-term outcomes, and assess various definitions of REM in adalimumab (ADA) long-term trials. Methods Data are from 2 trials of ADA in early RA pts; In PREMIER, pts received ADA, methotrexate (MTX) or ADA+MTX for 2 years (yrs), after which they could enter an open label (OL) period for upto 8 yrs2. In OPTIMA, pts received ADA+MTX, or placebo (PBO) +MTX for 26 weeks (wks). Based on whether or not pts achieved DAS28-CRP <3.2 at wks 22 and 26, pts withdrew ADA, continued on PBO+MTX, ADA+MTX or OL ADA+MTX until Wk 783. For this analysis, non-sustained REM/disease control was defined as meeting one of the following at 6 months but not 1 yr: DAS28-CRP <2.6; simplified disease activity index (SDAI) ≤3.3; clinical disease activity index (CDAI) ≤2.8. Sustained REM/disease control was defined as meeting these criteria at both 6 months and 1 yr. The mean change from baseline in health assessment questionnaire- disability index (ΔHAQ-DI), or modified total Sharp score (ΔmTSS), and the number of pts without clinical worsening of HAQ-DI (Δ≤0.22) were assessed over 78 wks for OPTIMA, or 5 yrs for PREMIER. NRI and LOCF were used for binary and continuous variables, respectively. Results In OPTIMA, by any of the REM criteria, pts in sustained REM had larger mean ΔHAQ-DI over time (Fig 1A) vs pts in non-sustained REM. Pts with non-sustained DAS28-CRP <2.6 vs non-sustained CDAI REM had numerically smaller ΔHAQ-DI up to Wk 52. Over time, more pts in sustained vs non-sustained REM using DAS28-CRP<2.6 (but not CDAI or SDAI criteria) did not have clinical worsening of HAQ-DI, possibly due to more suppression of inflammatory components upon achieving CDAI REM but not DAS28-CRP <2.6 in these early RA pts (Fig 1B). At Wk 78, ΔmTSS at Wk 78 was smaller for pts in sustained vs non-sustained DAS28-CRP <2.6, and similar for sustained and non-sustained CDAI REM (Fig 1C). Somewhat fewer pts at Wk 78 may have contributed to some variability. Trends were similar in PREMIER (not shown). Conclusions Pts who were in sustained disease control/REM had better clinical, functional and radiographic outcomes over the long- term, vs pts in a more transient state, regardless of the REM criteria used, although for CDAI REM, functional and radiographic outcomes were similar for sustained and non-sustained REM, in line with its higher stringency. References Aletaha et al, Arthritis & Rheum. 2009;5:1242. Breedveld et al. 2006. Arthritis & Rheum;54:26. Smolen et al. 2014. Lancet;383:321. Acknowledgements AbbVie: study sponsor, contributed to design, data collection, analysis, interpretation; and writing, reviewing, approval of final version. Medical writing: Naina Barretto, of AbbVie. Disclosure of Interest J. Smolen: None declared, C. Gabay Grant/research support from: AbbVie Inc, Amgen, BMS, MSD, Pfizer, Roche, Celgene, Sanofi, and Regeneron., Consultant for: AbbVie Inc, Amgen, BMS, MSD, Pfizer, Roche, Celgene, Sanofi, and Regeneron., D. Aletaha Grant/research support from: AbbVie Inc., Pfizer, Grünenthal, Merck, Medac, UCB, Mitsubishi/Tanabe, Janssen, and Roche., Consultant for: AbbVie Inc., Pfizer, Grünenthal, Merck, Medac, UCB, Mitsubishi/Tanabe, Janssen, and Roche., P. Emery Grant/research support from: research grants and consulting fees from Pfizer, MSD, AbbVie Inc., Bristol-Myers Squibb, UCB, Roche, Novartis, Samsung, Sandoz and Lilly., Consultant for: research grants and consulting fees from Pfizer, MSD, AbbVie Inc., Bristol-Myers Squibb, UCB, Roche, Novartis, Samsung, Sandoz and Lilly., I. Sainsbury Employee of: AbbVie, Y. Zhang Employee of: AbbVie, A. Kavanaugh Grant/research support from: AbbVie Inc., Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB., Consultant for: AbbVie Inc., Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB.